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Zhong Pei - One of the best experts on this subject based on the ideXlab platform.
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Vagus Nerve Stimulation Attenuates Cerebral Microinfarct and Colitis-induced Cerebral Microinfarct Aggravation in Mice
Frontiers in neurology, 2018Co-Authors: Xiaofeng Chen, Yu-kun Feng, Fengyin Liang, Taotao Shi, Shijian Luo, Ruxun Huang, Zhong PeiAbstract:Cerebral cortical Microinfarct (CMI) is common in patients with dementia and cognitive decline. Emerging studies reported that intestinal dysfunction influenced the outcome of ischemic stroke and that vagus nerve stimulation (VNS) protected against ischemic stroke. However, the effects of intestinal dysfunction and VNS on CMI are not clear. Therefore, we examined the influence of colitis and VNS on CMI and the mechanisms of VNS attenuating CMI in mice with colitis. CMI was induced using a two-photon laser. Colitis was induced using oral dextran sodium sulfate (DSS). The cervical vagus nerve was stimulated using a constant current. In vivo blood-brain barrier (BBB) permeability was evaluated using two-photon imaging. Infarct volume, microglial and astrocyte activation, oxidative stress and proinflammatory cytokine levels were assessed using immunofluorescent and immunohistochemical staining. The BBB permeability, infarct volume, activation of microglia and astrocytes and oxidative stress increased significantly in mice with colitis and CMI compared to those in mice with CMI. However, these processes were reduced in CMI mice when VNS was performed. Brain lesions in mice with colitis and CMI were significantly ameliorated when VNS was performed during the acute phase of colitis. Our study demonstrated that VNS alleviated CMI and this neuroprotection was associated with the suppression of BBB permeability, neuroinflammation and oxidative stress. Also, our results indicated that VNS reduced colitis-induced microstroke aggravation.
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Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction.
EBioMedicine, 2018Co-Authors: Chuanming Luo, Fengyin Liang, Huixia Ren, Xiaoli Yao, Zhe Shi, Jing X. Kang, Jian-bo Wan, Zhong PeiAbstract:Abstract Cerebral Microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of Microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical Microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse Microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of Microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating Microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical Microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the Microinfarct size. The protective effects of ω-3 PUFAs against Microinfarcts were further verified in a multiple diffuse Microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse Microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing Microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia.
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Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction
Elsevier, 2018Co-Authors: Chuanming Luo, Fengyin Liang, Huixia Ren, Xiaoli Yao, Zhe Shi, Jing X. Kang, Jian-bo Wan, Zhong PeiAbstract:Cerebral Microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of Microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical Microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse Microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of Microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating Microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical Microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the Microinfarct size. The protective effects of ω-3 PUFAs against Microinfarcts were further verified in a multiple diffuse Microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse Microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing Microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia. Keywords: Fish oil, Cognitive decline, Vascular dementia, Neuropsychiatric disorder
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A mouse cerebral cortical Microinfarct model induced by ultrashort laser irradiation wih two-photon microscopy
2017Co-Authors: Taotao Shi, Yu-kun Feng, Shijian Luo, Chaogang Tang, Xiaofeng Chen, Ruxun Huang, Zhong PeiAbstract:Objective To verify the reliability of the mouse model of cerebral cortical Microinfarct induced by two-photon microscopy and to explore its pathological changes. Methods Seventeen male C57BL/6J mice were randomly divided into a Microinfarct group (n=11) or a sham operation group (n=6). A thinned cranial window of 3 mm diameter was performed over the cerebral cortex with a high-speed micro-drill until the small blood vessels were clearly observed under a dissecting microscope. Then, a permanent single cortical penetrating arteriole occlusion was induced with a gradually enhanced ultrashort laser irradiation through the thinned cranial window with two-photon microscopy. At 7 days after modeling, the cerebral Microinfarct volume was measured with HE staining, and the neuron loss, activation of glial cells and deposition of 3-nitrotyrosine were assessed using immunohistochemistry. Results The target vessels of cerebral cortex in 8 (72.7%) mice were occluded and the Microinfarcts formed in the Microinfarct group, and the average Microinfarct volume was 317.23±20.29 μm3. There were remarkable neuron loss and microglia infiltration in the infarcted core, a large number of reactive astrocytes surrounding the infarcted lesion, and massive deposition of 3-nitrotyrosine in the peri-infarct area. No infarcts were observed in the sham operation group. The deposition of 3-nitrotyrosine in the sham operation group was significantly less than that in the Microinfarct group (8.00±1.48 vs. 98.38±9.10; t=23.962, P
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a mouse cerebral cortical Microinfarct model induced by ultrashort laser irradiation wih two photon microscopy
Int J Cerebrovasc Dis, 2017Co-Authors: Taotao Shi, Yu-kun Feng, Shijian Luo, Chaogang Tang, Xiaofeng Chen, Ruxun Huang, Zhong PeiAbstract:Objective To verify the reliability of the mouse model of cerebral cortical Microinfarct induced by two-photon microscopy and to explore its pathological changes. Methods Seventeen male C57BL/6J mice were randomly divided into a Microinfarct group (n=11) or a sham operation group (n=6). A thinned cranial window of 3 mm diameter was performed over the cerebral cortex with a high-speed micro-drill until the small blood vessels were clearly observed under a dissecting microscope. Then, a permanent single cortical penetrating arteriole occlusion was induced with a gradually enhanced ultrashort laser irradiation through the thinned cranial window with two-photon microscopy. At 7 days after modeling, the cerebral Microinfarct volume was measured with HE staining, and the neuron loss, activation of glial cells and deposition of 3-nitrotyrosine were assessed using immunohistochemistry. Results The target vessels of cerebral cortex in 8 (72.7%) mice were occluded and the Microinfarcts formed in the Microinfarct group, and the average Microinfarct volume was 317.23±20.29 μm3. There were remarkable neuron loss and microglia infiltration in the infarcted core, a large number of reactive astrocytes surrounding the infarcted lesion, and massive deposition of 3-nitrotyrosine in the peri-infarct area. No infarcts were observed in the sham operation group. The deposition of 3-nitrotyrosine in the sham operation group was significantly less than that in the Microinfarct group (8.00±1.48 vs. 98.38±9.10; t=23.962, P<0.001). Conclusions The mouse model of cerebral cortical Microinfarct induced by two-photon microscopy is reliable, and its histopathologic changes are consistent with the pathologic features of cerebral Microinfarct. Key words: Cerebral Infarction; Cerebral Cortex; Microscopy, Confocal; Neurons; Cell Death; Inflammation; Tyrosine; Disease Models, Animal; Mice
Geert Jan Biessels - One of the best experts on this subject based on the ideXlab platform.
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Author response: Clinical relevance of acute cerebral Microinfarcts in vascular cognitive impairment.
Neurology, 2020Co-Authors: Doeschka A. Ferro, Wiesje M. Van Der Flier, Frederik Barkhof, Hilde Van Den Brink, Lieza G. Exalto, Jooske M.f. Boomsma, Niels D. Prins, Geert Jan BiesselsAbstract:We read with interest the article by Ferro et al.1 that focused on acute cerebral Microinfarcts (ACMIs) in vascular cognitive impairment.
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Cerebral Microinfarcts affect brain structural network topology in cognitively impaired patients.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2020Co-Authors: Liwen Zhang, Geert Jan Biessels, Saima Hilal, Joanna Su Xian Chong, Siwei Liu, Hee Youn Shim, Eddie Chong, Zi Xuen Wong, Yng Miin LokeAbstract:Cerebral Microinfarcts (CMIs), a novel cerebrovascular marker, are prevalent in Alzheimer’s disease (AD) and associated with cognitive impairment. Nonetheless, the underlying mechanism of how CMIs ...
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Cortical Microinfarcts in memory clinic patients are associated with reduced cerebral perfusion.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2019Co-Authors: Doeschka A. Ferro, Susanne J Van Veluw, Hugo J. Kuijf, Saima Hilal, Narayanaswamy Venketasubramanian, Henri J.j.m. Mutsaerts, Esben Thade Petersen, Jan Petr, Tan Boon Yeow, Geert Jan BiesselsAbstract:Cerebral cortical Microinfarcts (CMIs) are small ischemic lesions associated with cognitive impairment and dementia. CMIs are frequently observed in cortical watershed areas suggesting that hypoperfusion contributes to their development. We investigated if presence of CMIs was related to a decrease in cerebral perfusion, globally or specifically in cortex surrounding CMIs. In 181 memory clinic patients (mean age 72 ± 9 years, 51% male), CMI presence was rated on 3-T magnetic resonance imaging (MRI). Cerebral perfusion was assessed from cortical gray matter of the anterior circulation using pseudo-continuous arterial spin labeling parameters cerebral blood flow (CBF) (perfusion in mL blood/100 g tissue/min) and spatial coefficient of variation (CoV) (reflecting arterial transit time (ATT)). Patients with CMIs had a 12% lower CBF (beta = -.20) and 22% higher spatial CoV (beta = .20) (both p
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Cortical Microinfarcts and White Matter Connectivity in Memory Clinic Patients
Frontiers in neurology, 2019Co-Authors: Doeschka A. Ferro, Geert Jan Biessels, Hugo J. Kuijf, Rutger Heinen, Bruno M. De Brito Robalo, Yael D ReijmerAbstract:Background and purpose: Cerebral Microinfarcts (CMIs) are associated with cognitive impairment and dementia. CMIs might affect cognitive performance through disruption of cerebral networks. We investigated in memory clinic patients whether cortical CMIs are clustered in specific brain regions and if presence of cortical CMIs is associated with reduced white matter (WM) connectivity in tracts projecting to these regions. Methods: 164 memory clinic patients with vascular brain injury with a mean age of 72 ± 11 years (54% male) were included. All underwent 3 tesla MRI, including a diffusion MRI and cognitive testing. Cortical CMIs were rated according to established criteria and their spatial location was marked. Diffusion imaging-based tractography was used to reconstruct WM connections and voxel based analysis (VBA) to assess integrity of WM directly below the cortex. WM connectivity and integrity were compared between patients with and without cortical CMIs for the whole brain and regions with a high CMI burden. Results: 30 patients (18%) had at least 1 cortical CMI [range 1–46]. More than 70% of the cortical CMIs were located in the superior frontal, middle frontal, and pre- and postcentral brain regions (covering 16% of the cortical surface). In these high CMI burden regions, presence of cortical CMIs was not associated with WM connectivity after correction for conventional neuroimaging markers of vascular injury. WM connectivity in the whole brain and WM voxels directly underneath the cortical surface did not differ between patients with and without cortical CMIs. Conclusion: Cortical CMIs displayed a strong local clustering in highly interconnected frontal, pre- and postcentral brain regions. Nevertheless, WM connections projecting to these regions were not disproportionally impaired in patients with compared to patients without cortical CMIs. Alternative mechanisms, such as focal disturbances in cortical structure and functioning, may better explain CMI associated cognitive impairment.
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Clinical relevance of acute cerebral Microinfarcts in vascular cognitive impairment.
Neurology, 2019Co-Authors: Doeschka A. Ferro, Frederik Barkhof, Hilde Van Den Brink, Lieza G. Exalto, Jooske M.f. Boomsma, Niels D. Prins, Wiesje Van Der Flier, Geert Jan BiesselsAbstract:OBJECTIVE: To determine the occurrence of acute cerebral Microinfarcts (ACMIs) in memory clinic patients and relate their presence to vascular risk and cognitive profile, CSF and neuroimaging markers, and clinical outcome. METHODS: The TRACE-VCI study is a memory clinic cohort of patients with vascular brain injury on MRI (i.e., possible vascular cognitive impairment [VCI]). We included 783 patients (mean age 67.6 ± 8.5, 46% female) with available 3T diffusion-weighted imaging (DWI). ACMIs were defined as supratentorial DWI hyperintensities
Fengyin Liang - One of the best experts on this subject based on the ideXlab platform.
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Overexpression of Slit2 decreases neuronal excitotoxicity, accelerates glymphatic clearance, and improves cognition in a multiple Microinfarcts model.
Molecular brain, 2020Co-Authors: Fengyin Liang, Xi ChenAbstract:BACKGROUND Cerebral Microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. One possibility is the dysfunction of GABAergic transmission and ensuing excitotoxicity. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown. The secreted leucine-rich repeat (LRR) family protein slit homologue 2 (Slit2) upregulates GABAergic activity and protects against global cerebral ischemia, but the neuroprotective efficacy of Slit2 against MIs has not been examined. METHODS Middle-aged Wild type (WT) and Slit2-Tg mice were divided into sham and MI treatment groups. MIs were induced in parietal cortex by laser-evoked arteriole occlusion. Spatial memory was then compared between sham and MI groups using the Morris water maze (MWM) task. In addition, neuronal activity, blood brain barrier (BBB) permeability, and glymphatic clearance in peri-infarct areas were compared using two-photon imaging, while GABAergic transmission, microglial activation, neuronal loss, and altered cortical connectivity were compared by immunofluorescent staining or western blotting. RESULTS Microinfarcts increased the amplitude and frequency of spontaneous intracellular Ca2+ signals, reduced neuronal survival and connectivity within parietal cortex, decreased the number of GABAergic interneurons and expression of vesicular GABA transporter (VGAT), induced neuroinflammation, and impaired both glymphatic clearance and spatial memory. Alternatively, Slit2 overexpression attenuated dysfunctional neuronal Ca2+ signaling, protected against neuronal death in the peri-infarct area as well as loss of parietal cortex connectivity, increased GABAergic interneuron number and VGAT expression, attenuated neuroinflammation, and improved both glymphatic clearance and spatial memory. CONCLUSION Our results strongly suggest that overexpression of Slit2 protected against the dysfunction in MIs, which is a potential therapeutic target for cognition impairment in the elderly.
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Cortical Microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity
2020Co-Authors: Yi-wei Feng, Yu-kun Feng, Fengyin Liang, Guan Yalun, Liu Shuhua, Yu ZhangAbstract:Microinfarcts are common among the elderly, and patients with Microinfarcts are more vulnerable to another stroke. However, the potential effect of Microinfarct on recurrent stroke remains elusive. In this study, we investigated the detrimental effect of Microinfarct on recurrent stroke in mice. Microinfarct was induced using two-photon laser and photothrombotic stroke was induced in the cortex contralateral to Microinfarct four weeks later. We found that CMI could trigger the formation of innate immune memory, which exacerbated the pro-inflammatory response and ischemic injury in second photothrombotic stroke. Furthermore, we clarified the role of NLRP3 inflammasome in the nuclei of microglia, which interacts with the MLL1 complex and thereby increases H3K4 methylation, suggesting that NLRP3 is critical in Microinfarct-induced innate immune memory. Additionally, NLRP3 knockout in microglia attenuated Microinfarct-induced detrimental effects on recurrent stroke. Our study highlights the detrimental effect of trained immunity on the recurrent stroke and reveals the important role of NLRP3 in mediating the formation of this memory, which may be a therapeutic target to mitigate recurrent strokes.
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Vagus Nerve Stimulation Attenuates Cerebral Microinfarct and Colitis-induced Cerebral Microinfarct Aggravation in Mice
Frontiers in neurology, 2018Co-Authors: Xiaofeng Chen, Yu-kun Feng, Fengyin Liang, Taotao Shi, Shijian Luo, Ruxun Huang, Zhong PeiAbstract:Cerebral cortical Microinfarct (CMI) is common in patients with dementia and cognitive decline. Emerging studies reported that intestinal dysfunction influenced the outcome of ischemic stroke and that vagus nerve stimulation (VNS) protected against ischemic stroke. However, the effects of intestinal dysfunction and VNS on CMI are not clear. Therefore, we examined the influence of colitis and VNS on CMI and the mechanisms of VNS attenuating CMI in mice with colitis. CMI was induced using a two-photon laser. Colitis was induced using oral dextran sodium sulfate (DSS). The cervical vagus nerve was stimulated using a constant current. In vivo blood-brain barrier (BBB) permeability was evaluated using two-photon imaging. Infarct volume, microglial and astrocyte activation, oxidative stress and proinflammatory cytokine levels were assessed using immunofluorescent and immunohistochemical staining. The BBB permeability, infarct volume, activation of microglia and astrocytes and oxidative stress increased significantly in mice with colitis and CMI compared to those in mice with CMI. However, these processes were reduced in CMI mice when VNS was performed. Brain lesions in mice with colitis and CMI were significantly ameliorated when VNS was performed during the acute phase of colitis. Our study demonstrated that VNS alleviated CMI and this neuroprotection was associated with the suppression of BBB permeability, neuroinflammation and oxidative stress. Also, our results indicated that VNS reduced colitis-induced microstroke aggravation.
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Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction.
EBioMedicine, 2018Co-Authors: Chuanming Luo, Fengyin Liang, Huixia Ren, Xiaoli Yao, Zhe Shi, Jing X. Kang, Jian-bo Wan, Zhong PeiAbstract:Abstract Cerebral Microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of Microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical Microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse Microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of Microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating Microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical Microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the Microinfarct size. The protective effects of ω-3 PUFAs against Microinfarcts were further verified in a multiple diffuse Microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse Microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing Microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia.
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Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction
Elsevier, 2018Co-Authors: Chuanming Luo, Fengyin Liang, Huixia Ren, Xiaoli Yao, Zhe Shi, Jing X. Kang, Jian-bo Wan, Zhong PeiAbstract:Cerebral Microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of Microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical Microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse Microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of Microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating Microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical Microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the Microinfarct size. The protective effects of ω-3 PUFAs against Microinfarcts were further verified in a multiple diffuse Microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse Microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing Microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia. Keywords: Fish oil, Cognitive decline, Vascular dementia, Neuropsychiatric disorder
Chuanming Luo - One of the best experts on this subject based on the ideXlab platform.
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Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction.
EBioMedicine, 2018Co-Authors: Chuanming Luo, Fengyin Liang, Huixia Ren, Xiaoli Yao, Zhe Shi, Jing X. Kang, Jian-bo Wan, Zhong PeiAbstract:Abstract Cerebral Microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of Microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical Microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse Microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of Microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating Microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical Microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the Microinfarct size. The protective effects of ω-3 PUFAs against Microinfarcts were further verified in a multiple diffuse Microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse Microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing Microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia.
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Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction
Elsevier, 2018Co-Authors: Chuanming Luo, Fengyin Liang, Huixia Ren, Xiaoli Yao, Zhe Shi, Jing X. Kang, Jian-bo Wan, Zhong PeiAbstract:Cerebral Microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of Microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical Microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse Microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of Microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating Microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical Microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the Microinfarct size. The protective effects of ω-3 PUFAs against Microinfarcts were further verified in a multiple diffuse Microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse Microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing Microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia. Keywords: Fish oil, Cognitive decline, Vascular dementia, Neuropsychiatric disorder
Yael D Reijmer - One of the best experts on this subject based on the ideXlab platform.
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Histopathology of diffusion-weighted imaging-positive lesions in cerebral amyloid angiopathy
Acta Neuropathologica, 2020Co-Authors: Annemieke Telgte, Yael D Reijmer, Matthew P Frosch, Ashley A. Scherlek, Brian J. Bacskai, Andre J. Kouwe, Thijs Harten, Marco Duering, Frank-erik Leeuw, Steven M. GreenbergAbstract:Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute Microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI—ex vivo MRI—histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions post-mortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI−/T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls ( p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute Microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute Microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute Microinfarcts post-mortem, which may benefit future histopathological investigations on the etiology of Microinfarcts.
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Cortical Microinfarcts and White Matter Connectivity in Memory Clinic Patients
Frontiers in neurology, 2019Co-Authors: Doeschka A. Ferro, Geert Jan Biessels, Hugo J. Kuijf, Rutger Heinen, Bruno M. De Brito Robalo, Yael D ReijmerAbstract:Background and purpose: Cerebral Microinfarcts (CMIs) are associated with cognitive impairment and dementia. CMIs might affect cognitive performance through disruption of cerebral networks. We investigated in memory clinic patients whether cortical CMIs are clustered in specific brain regions and if presence of cortical CMIs is associated with reduced white matter (WM) connectivity in tracts projecting to these regions. Methods: 164 memory clinic patients with vascular brain injury with a mean age of 72 ± 11 years (54% male) were included. All underwent 3 tesla MRI, including a diffusion MRI and cognitive testing. Cortical CMIs were rated according to established criteria and their spatial location was marked. Diffusion imaging-based tractography was used to reconstruct WM connections and voxel based analysis (VBA) to assess integrity of WM directly below the cortex. WM connectivity and integrity were compared between patients with and without cortical CMIs for the whole brain and regions with a high CMI burden. Results: 30 patients (18%) had at least 1 cortical CMI [range 1–46]. More than 70% of the cortical CMIs were located in the superior frontal, middle frontal, and pre- and postcentral brain regions (covering 16% of the cortical surface). In these high CMI burden regions, presence of cortical CMIs was not associated with WM connectivity after correction for conventional neuroimaging markers of vascular injury. WM connectivity in the whole brain and WM voxels directly underneath the cortical surface did not differ between patients with and without cortical CMIs. Conclusion: Cortical CMIs displayed a strong local clustering in highly interconnected frontal, pre- and postcentral brain regions. Nevertheless, WM connections projecting to these regions were not disproportionally impaired in patients with compared to patients without cortical CMIs. Alternative mechanisms, such as focal disturbances in cortical structure and functioning, may better explain CMI associated cognitive impairment.
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Microbleed and Microinfarct detection in amyloid angiopathy: a high-resolution MRI-histopathology study.
Brain : a journal of neurology, 2016Co-Authors: Susanne J Van Veluw, Andreas Charidimou, Andre J Van Der Kouwe, Arne Lauer, Yael D Reijmer, Isabel Costantino, M Edip Gurol, Geert Jan Biessels, Matthew P Frosch, Anand ViswanathanAbstract:Cerebral amyloid angiopathy is a common neuropathological finding in the ageing human brain, associated with cognitive impairment. Neuroimaging markers of severe cerebral amyloid angiopathy are cortical microbleeds and Microinfarcts. These parenchymal brain lesions are considered key contributors to cognitive impairment. Therefore, they are important targets for therapeutic strategies and may serve as surrogate neuroimaging markers in clinical trials. We aimed to gain more insight into the pathological basis of magnetic resonance imaging-defined microbleeds and Microinfarcts in cerebral amyloid angiopathy, and to explore the pathological burden that remains undetected, by using high and ultra-high resolution ex vivo magnetic resonance imaging, as well as detailed histological sampling. Brain samples from five cases (mean age 85 ± 6 years) with pathology-proven cerebral amyloid angiopathy and multiple microbleeds on in vivo clinical magnetic resonance imaging were subjected to high-resolution ex vivo 7 T magnetic resonance imaging. On the obtained high-resolution (200 μm isotropic voxels) ex vivo magnetic resonance images, 171 microbleeds were detected compared to 66 microbleeds on the corresponding in vivo magnetic resonance images. Of 13 sampled microbleeds that were matched on histology, five proved to be acute and eight old microhaemorrhages. The iron-positive old microhaemorrhages appeared approximately four times larger on magnetic resonance imaging compared to their size on histology. In addition, 48 Microinfarcts were observed on ex vivo magnetic resonance imaging in three out of five cases (two cases exhibited no Microinfarcts). None of them were visible on in vivo 1.5 T magnetic resonance imaging after a retrospective analysis. Of nine sampled Microinfarcts that were matched on histology, five were confirmed as acute and four as old Microinfarcts. Finally, we explored the proportion of microhaemorrhage and Microinfarct burden that is beyond the detection limits of ex vivo magnetic resonance imaging, by scanning a smaller sample at ultra-high resolution, followed by serial sectioning. At ultra-high resolution (75 μm isotropic voxels) magnetic resonance imaging we observed an additional 48 microbleeds (compared to high resolution), which proved to correspond to vasculopathic changes (i.e. morphological changes to the small vessels) instead of frank haemorrhages on histology. After assessing the serial sections of this particular sample, no additional haemorrhages were observed that were missed on magnetic resonance imaging. In contrast, nine Microinfarcts were found in these sections, of which six were only retrospectively visible at ultra-high resolution. In conclusion, these findings suggest that microbleeds on in vivo magnetic resonance imaging are specific for microhaemorrhages in cerebral amyloid angiopathy, and that increasing the resolution of magnetic resonance images results in the detection of more 'non-haemorrhagic' pathology. In contrast, the vast majority of Microinfarcts currently remain under the detection limits of clinical in vivo magnetic resonance imaging.
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Estimating Total Cerebral Microinfarct Burden From Diffusion-Weighted Imaging
Stroke, 2015Co-Authors: Eitan Auriel, Matt T. Bianchi, Yael D Reijmer, Matthew P Frosch, M. Brandon Westover, Sergi Martinez-ramirez, Ellis S. Van Etten, Panagiotis Fotiadis, Kris SchwabAbstract:Background and Purpose—Cerebral Microinfarcts (CMI) are important contributors to vascular cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. We aim to describe a mathematical method for estimating total number of CMI based on the presence of incidental DWI lesions. Methods—We reviewed magnetic resonance imaging scans of subjects with cognitive decline, cognitively normal subjects and previously reported subjects with past intracerebral hemorrhage (ICH). Based on temporal and spatial characteristics of DWI lesions, we estimated the annual rate of CMI needed to explain the observed rate of DWI lesion detection in each group. To confirm our estimates, we performed extensive sampling for CMI in the brain of a deceased subject with past lobar ICH who found to have a DWI lesion during life. Results—Clinically silent DWI lesions were present in 13 of 343 (3.8%) cognitively impaired and 10 of 199 (5%) cognitively intact n...
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Microinfarct disruption of white matter structure a longitudinal diffusion tensor analysis
Neurology, 2014Co-Authors: Eitan Auriel, Yael D Reijmer, Panagiotis Fotiadis, Brian L Edlow, S Ramirezmartinez, Anne Reed, Anastasia Vashkevich, K Schwab, Jonathan Rosand, Anand ViswanathanAbstract:Objective: To evaluate the local effect of small asymptomatic infarctions detected by diffusion-weighted imaging (DWI) on white matter microstructure using longitudinal structural and diffusion tensor imaging (DTI). Methods: Nine acute to subacute DWI lesions were identified in 6 subjects with probable cerebral amyloid angiopathy who had undergone high-resolution MRI both before and after DWI lesion detection. Regions of interest (ROIs) corresponding to the site of the DWI lesion (lesion ROI) and corresponding site in the nonlesioned contralateral hemisphere (control ROI) were coregistered to the pre- and postlesional scans. DTI tractography was additionally performed to reconstruct the white matter tracts containing the ROIs. DTI parameters (fractional anisotropy [FA], mean diffusivity [MD]) were quantified within each ROI, the 6-mm lesion-containing tract segments, and the entire lesion-containing tract bundle. Lesion/control FA and MD ratios were compared across time points. Results: The postlesional scans (performed a mean 7.1 ± 4.7 months after DWI lesion detection) demonstrated a decrease in median FA lesion/control ROI ratio (1.08 to 0.93, p = 0.038) and increase in median MD lesion/control ROI ratio (0.97 to 1.17, p = 0.015) relative to the prelesional scans. There were no visible changes on postlesional high-resolution T1-weighted and fluid-attenuated inversion recovery images in 4 of 9 lesion ROIs and small (2–5 mm) T1 hypointensities in the remaining 5. No postlesional changes in FA or MD ratios were detected in the 6-mm lesion-containing tract segments or full tract bundles. Conclusions: Asymptomatic DWI lesions produce chronic local microstructural injury. The cumulative effects of these widely distributed lesions may directly contribute to small-vessel–related vascular cognitive impairment.